Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
  • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
  • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
  • C07D243/24—Oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to a series of anti-viral benzodiazepine derivatives.
• it relates to a series of benzodiazepine derivatives which interact with an inhibitor of the RSV fusion protein to provide an additive or synergistic therapeutic effect in treating or preventing an RSV infection.
• Respiratory Syncytial Virus is a major cause of respiratory illness in patients of all ages. In adults, it tends to cause mild cold symptoms. In school-aged children, it can cause a cold and bronchial cough. In infants and toddlers it can cause bronchiolitis (inflammation of the smaller airways of the lungs) or pneumonia. It has also been found to be a frequent cause of middle ear infections (otitis media) in pre-school children. RSV infection in the first year of life has been implicated in the development of asthma during childhood.
• palivizumab a monoclonal antibody to RSV
• palivizumab a monoclonal antibody to RSV
• This antibody is often effective, it is expensive. Indeed, its expense means that it is unavailable for many people in need of anti-RSV therapy. There is therefore an urgent need for effective alternatives to existing anti-RSV therapy.
• Small compounds which inhibit RSV replication by inhibiting the fusion (F) protein of RSV block the entry of the virus into the host cell and the exit from the host cell via syncytia formation. While these compounds have been shown to have high potency, RSV rapidly develops resistance to these compounds through mutations in the F protein (Morton, C. J. et al, 2003.Virology 311, 275-288).
• PCT/GB03/04050 filed on 20 Sep. 2003 discloses a series of benzodiazepine derivatives which inhibit RSV replication. Serial passaging experiments have indicated that resistance to these inhibitors is slow to develop and sequencing of resistant mutants did not reveal any significant changes in the F protein. It can therefore be assumed that these benzodiazepines have a common and novel mode of action, which does not involve inhibition of the F-protein.
• the present invention therefore provides, in a first embodiment, a pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and
• components (a) and (b) have at least an additive effect.
• the concepts of synergism and additivity are, of course, well known in the field of pharmacology. It is thus well established that a therapeutically useful additive combination is one in which the effect of the combination is greater than the larger of the effects produced by each of the components at the same concentrations as in the mixture.
• a given formulation containing x wt % of component (a) and y wt % of component (b) has an activity which is at least as great as the activity of a formulation containing, as sole active ingredient, either x wt % component (a) or y wt % component (b).
• the active ingredients are typically operating via different physiological pathways.
• component (a) and component (b) are believed to be inhibiting separate RSV proteins.
• An additive combination is therapeutically useful because it can achieve a therapeutically useful effect using lower concentrations of each active component. This enables the side-effects of the medication to be minimised.
• the additive combination can be formulated so that each active ingredient is present at a concentration which is subclinical in cells other than the target disease cells. The additive combination is nevertheless therapeutically effective in target cells which respond to both ingredients.
• an inhibitor of the RSV fusion protein can be identified by an assay comprising:
• any increase in fluorescence signifies a fusion event.
• 100% inhibition is achieved.
• a control of growth medium and solvent e.g., growth medium with 10% fetal bovine serum and DMSO
• 0% inhibition is achieved.
• the % inhibition achieved with the candidate fusion protein inhibitor can be determined by quantitative assessment of the fluorescence in step (f).
• component (a) is typically a compound which achieves at least 10%, more typically at least 30%, preferably at least 50% and most preferably at least 75%, inhibition of the RSV fusion protein as determined by the above assay.
• component (a) is a compound of formula (1), or a pharmaceutically acceptable salt thereof,
• A is C or N, optionally substituted with H, halogen, C 1-6 alkyl, C 2-6 alkenyl, cyano-C 1-6 alkyl, CO 2 R 4 , aryl, benzoaminocarbonyl, hydroxybenzyl, SO 2 NR 4 R 5 or C 3-6 cycloalkyl.
• A is carbon, it may also be optionally substituted by O or S via a double bond;
• B is C or N; where B is C it may be optionally substituted by H, C 1-6 alkyl, NO 2 , CN, halogen, COR 4 , COOR 4 , CONHR 4 C( ⁇ NH)NH 2 or C( ⁇ NOH)NH 2 .
• R 1 , R 2 and R 3 are hydrogen, and the other is hydrogen or —C(NH)—NH 2 .
• all of R 1 , R 2 and R 3 are hydrogen.
• —X—Y is H, or X is a C 1 -C 6 alkylene group which is unsubstituted or substituted by a hydroxy group and Y is H, OH, CN, —NR′R′′, —COR′, —SO 2 R′ or phenyl, wherein R′ and R′′ are the same or different and represent a C 1 -C 4 alkyl group.
• Z is —CH 2 —.
• Q is a moiety
• B is —CH— or —N—
• a 1 is —C(O)— or —NH—
• a 2 is —CH 2 —, —CHR′— or —NR′′—
• R′ is a halogen atom and R′′ represents a hydrogen atom or a C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, SO 2 —(C 1 -C 6 alkyl), —SO 2 —N(C 1 -C 6 alkyl) 2 or —(CO—NH) a —(C 1 -C 4 alkyl)-phenyl group, wherein a is 0 or 1, which group is unsubstituted or is substituted with a hydroxy or cyano substituent.
• Particularly preferred compounds of the invention are compounds of formula (Ia) and pharmaceutically acceptable salts thereof
• Component (a) can also be a compound of formula (II), or a pharmaceutically acceptable salt thereof,
• L 1 is —CH 2 —.
• L 2 is —NH—.
• R 1 is methyl or hydroxy.
• n is 2.
• each R 1 is different.
• Y is C 1 -C 4 alkyl.
• Z is —NH 2 .
• Component (a) can also be a compound of formula (III), or a pharmaceutically acceptable salt thereof,
• Component (a) can also be a compound of formula (IV), or a pharmaceutically acceptable salt thereof.
• the compound of formula (IV) is 4,4′-Bis-(4,6-bis- ⁇ 3-[bis-(2-carbamoyl-ethyl)-sulfamoyl]-phenylamino ⁇ -[1,3,5]triazin-2-ylamino)-biphenyl-2,2′-disulfonic acid.
• component (a) is:
• the composition contains an RSV fusion inhibitor, as described above, and a benzodiazepine identifiable as having anti-RSV activity by the method of Example 8.
• component (b) is a compound of formula (V), or a pharmaceutically acceptable salt thereof,
• a C 1-6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C 1-4 alkyl group or moiety.
• Examples of C 1-4 alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
• the alkyl moieties may be the same or different.
• a hydroxyalkyl group is typically a said alkyl group that is substituted by one or more hydroxy groups. Typically, it is substituted by one, two or three hydroxy groups. Preferably, it is substituted by a single hydroxy group.
• Preferred hydroxyalkyl groups are (monohydroxy)ethyl groups.
• an acyl group is a C 2-7 acyl group, for example a group —CO—R, wherein R is a said C 1-6 alkyl group.
• an aryl group is typically a C 6-10 aryl group such as phenyl or naphthyl. Phenyl is preferred. An aryl group may be unsubstituted or substituted at any position. Typically, it carries 0, 1, 2 or 3 substituents.
• Suitable substitutents on an aryl group include halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl, di(C 1-6 alkyl)carbamoyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′, —S(O)NR′R′′, —S(O) 2 NR′R′′—NH—S(O) 2 R′ or —NH—CO—R′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-6 alkyl.
• substituents on an aryl group include halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl, di(C 1-6 alkyl)carbamoyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′′, —S(O)NR′R′′, —NH—S(O) 2 R′ or —NH—CO—R′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-6 alkyl.
• Preferred substituents on an aryl group include halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro, cyano, —CO 2 R′, —S(O)R′, —S(O) 2 R′ and —S(O) 2 NR′R′′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-4 alkyl.
• Examples of preferred substituents on an aryl group include halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro and cyano.
• substituents include fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 2-4 acyl, hydroxy, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, mono(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, nitro, —CO 2 R′, —S(O) 2 R′ and —S(O) 2 NH 2 , wherein R′ represents C 1-2 alkyl.
• substituents include fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and nitro.
• references to an aryl group include fused ring systems in which an aryl group is fused to a monocyclic carbocyclyl, heterocyclyl or heteroaryl group or to a fused group which is a monocyclic carbocyclyl, heterocyclyl or heteroaryl group which is fused to a phenyl ring.
• said fused ring systems are systems in which an aryl group is fused to a monocyclic carbocyclyl, heterocyclyl or heteroaryl group.
• Preferred such ring systems are those wherein an aryl group is fused to a fused group which is a monocyclic heterocyclyl or heteroaryl group or to a monocyclic carbocyclic group fused to a phenyl ring, in particular those wherein an aryl group is fused to a heterocyclyl or heteroaryl group.
• fused ring systems are groups in which a phenyl ring is fused to a thienyl group or to a tetrahydrofuranyl group to form a benzothienyl or dihydrobenzofuranyl group.
• fused rings are groups in which a phenyl ring is fused to a dioxanyl group, a pyrrolyl group or a 2,3-dihydroinden-1-one group to form a benzodioxinyl, indolyl or a 9H-fluoren-9-one group.
• a carbocyclyl group is a non-aromatic saturated or unsaturated monocyclic hydrocarbon ring, typically having from 3 to 6 carbon atoms.
• a saturated hydrocarbon ring i.e. a cycloalkyl group
• Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It is preferably cyclopentyl or cyclohexyl.
• a cycloalkyl group may be unsubstituted or substituted at any position. Typically, it carries 0, 1, 2 or 3 substituents.
• Suitable substitutents on a carbocyclyl group include halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl-, di(C 1-6 alkyl)carbamoyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, oxo, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′, —S(O)NR′R′′, —S(O) 2 NR′R′′, —NH—S(O) 2 R′ or —NH—CO—R′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-6 alkyl
• Suitable substitutents on a carbocyclyl group include halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl, di(C 1-6 alkyl)carbamoyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′, —S(O)NR′R′′, —NH—S(O) 2 R′ or —NH—CO—R′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-4 alkyl.
• Preferred substituents on an carbocyclyl group include halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro, cyano and oxo.
• Examples of preferred substituents on an carbocyclyl group include halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro and cyano.
• Particularly preferred substituents include fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, nitro and oxo.
• Examples of particularly preferred substituents include fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and nitro.
• Further examples of particularly preferred substituents include fluorine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and nitro.
• a heterocyclyl group is a non-aromatic saturated or unsaturated carbocyclic ring typically having from 5 to 10 carbon atoms, in which one or more, for example 1, 2 or 3, of the carbon atoms is replaced by a heteroatom selected from N, O and S. Saturated heterocyclyl groups are preferred.
• Examples include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl and thioxanyl. Further examples include dithiolanyl, oxazolidinyl, tetrahydrothiopyranyl and dithianyl. Piperazinyl, piperidinyl and morpholinyl are preferred.
• references to a heterocyclyl group include fused ring systems in which a heterocyclyl group is fused to a phenyl group.
• Preferred such fused ring systems are those wherein a 5- to 6-membered heterocyclyl group is fused to a phenyl group.
• An example of such a fused ring system is a group wherein a 1H-imidazol-2(3H)-onyl group or a imidazolidin-2-onyl group is fused to a phenyl ring to form a 1H-benzo[d]imidazol-2(3H)-onyl group.
• a heterocyclyl group is monocyclic.
• a heterocyclic group may be unsubstituted or substituted at any position. Typically, it carries 0, 1 or 2 substituents.
• Suitable substitutents on a heterocyclyl group include halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl, di(C 1-6 alkyl)carbomyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, oxo, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′, —S(O)NR′R′′, —S(O) 2 NR′R′′, —NH—S(O) 2 R′ or —NH—CO—R′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-6 alkyl.
• Suitable substitutents on a heterocyclyl group include halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl, di(C 1-6 alkyl)carbomyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′, —S(O)NR′R′′, —NH—S(O) 2 R′ or —NH—CO—R′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-6 alkyl.
• Preferred substituents on a heterocyclyl group include halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro, cyano and oxo.
• substituents on a heterocyclyl group include halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro and cyano.
• Particularly preferred substituents include fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, nitro and oxo.
• substituents include fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and nitro.
• substituents include fluorine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and nitro.
• a heterocyclyl group is unsubstituted or substituted by one or two C 1-2 alkyl groups.
• a halogen is typically chlorine, fluorine, bromine or iodine. It is preferably chlorine, fluorine or bromine. It is more preferably chlorine or fluorine.
• an alkoxy group is typically a said alkyl group attached to an oxygen atom.
• An alkylthio group is typically a said alkyl group attached to a thio group.
• a haloalkyl or haloalkoxy group is typically a said alkyl or alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
• Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as —CX 3 and —OCX 3 wherein X is a said halogen atom, for example chlorine or fluorine.
• Particularly preferred haloalkyl groups are —CF 3 and —CCl 3 .
• Particularly preferred haloalkoxy groups are —OCF 3 and —OCCl 3 .
• a heteroaryl group is typically a 5- to 10 membered aromatic ring, such as a 5- or 6-membered ring, containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N.
• heteroatoms for example 1, 2 or 3 heteroatoms, selected from O, S and N.
• examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, thiazolyl, imidazolyl and pyrazolyl groups. Further examples include oxazolyl and isothiazolyl.
• Preferred heteroaryl groups are pyridyl, thienyl, oxazolyl, isoxazolyl, furanyl and pyrazolyl.
• Examples of preferred heteroaryl groups are pyridyl, thienyl, isoxazolyl and furanyl.
• references to a heteroaryl groups include fused ring systems in which a heteroaryl group is fused to a phenyl group. Preferred such fused ring systems are those wherein a 5- to 6-membered heteroaryl group is fused to a phenyl group.
• fused ring systems examples include benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, benzoxazolyl, quinolinyl, quinazolinyl and isoquinolinyl moieties. Most preferably, however, a heterocyclyl group is monocyclic.
• a heteroaryl group may be unsubstituted or substituted at any position. Typically, it carries 0, 1, 2 or 3 substituents.
• Suitable substitutents on a heteroaryl group include halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl, di(C 1-6 alkyl)carbamoyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′, —S(O)NR′R′′, —S(O) 2 NR′R′′, —NH—S(O) 2 R′ or —NH—CO—R′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-6 alkyl.
• Suitable substitutents on a heteroaryl group include halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-4 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl, di(C 1-6 alkyl)carbamoyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′, —S(O)NR′R′′, —NH—S(O) 2 R′ or —NH—CO—R′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-6 alkyl.
• Preferred substituents on a heteroaryl group include halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro and cyano.
• Particularly preferred substituents include fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and nitro.
• Further preferred substituents include fluorine, chlorine, bromine, C 1-2 alkyl, C 1-2 haloalkyl and di(C 1-2 alkyl)amino.
• references to a heteroaryl group include fused ring systems in which a heteroaryl group is fused to a monocyclic said aryl, carbocyclyl or heterocyclyl group, or to a further heteroaryl group.
• Preferred such ring systems are those wherein a heteroaryl group is fused to an aryl group, for example a phenyl group.
• An example of such a fused ring system is a group wherein a thienyl group is fused to a phenyl ring to form a benzothienyl group.
• a further example of such a fused ring system is a group wherein a furanyl group is fused to a phenyl ring to form a benzofuranyl group.
• R 1 in the formula (V) is an aryl or heteroaryl group it is typically unsubstituted or substituted by one, two or three substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl or C 1-6 haloalkoxy.
• it is unsubstituted or substituted by one or two substituents selected from fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl or C 1-4 haloalkoxy.
• R 1 in the formula (V) is C 1-6 alkyl or aryl.
• R 1 is C 1-2 alkyl or aryl. More preferably, R 1 is C 1-2 alkyl or phenyl. More preferably, R 1 is phenyl.
• R 2 in the formula (V) is hydrogen or C 1-4 alkyl.
• R 2 is hydrogen.
• R 3 in the formula (V) is halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, mono(C 1-4 alkyl)amino or di(C 1-4 alkyl)amino.
• R 3 is fluorine, chlorine, bromine, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 alkylthio, C 1-2 haloalkyl, C 1-2 haloalkoxy, amino, mono(C 1-2 alkyl)amino or di(C 1-2 alkyl)amino.
• R 3 is methyl, trifluoromethyl, fluorine, chlorine or bromine.
• R 3 is methyl or chlorine.
• An example of a most preferred group is when R 3 is chlorine.
• n in the formula (V) is 0, 1 or 2.
• n is 0 or 1.
• R 4 in the formula (V) is hydrogen or C 1-4 alkyl.
• R 4 is hydrogen or C 1-2 alkyl. More preferably, R 4 is hydrogen or methyl. Most preferably, R 4 is hydrogen.
• R 5 in the formula (V) is a heterocyclyl group, it is typically attached via a carbon atom.
• R 5 is C 1-6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-4 alkyl)-, heteroaryl-(C 1-4 alkyl)-, carbocyclyl-(C 1-4 alkyl)-, heterocyclyl-(C 1-4 alkyl)-, aryl-C(O)—C(O)—, heteroaryl-C(O)—C(O)— or —XR 6 .
• R 5 groups are those wherein R 5 is C 1-6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-4 alkyl)-, heteroaryl-(C 1-4 alkyl)-, carbocyclyl-(C 1-4 alkyl)-, heterocyclyl-(C 1-4 alkyl)- or —XR 6 .
• R 5 in the formula (V) is C 1-4 alkyl, aryl, for example phenyl and dihydrobenzofuranyl, heteroaryl, for example thienyl, furanyl, isoxazolyl, pyridyl and benzothienyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, for example piperidinyl, morpholinyl and piperazinyl, phenyl-(C 1-2 alkyl)-, for example benzyl, heteroaryl-(C 1-2 alkyl)-, phenyl-C(O)—C(O)-, heteroaryl-C(O)—C(O)— or —XR 6 .
• aryl for example phenyl and dihydrobenzofuranyl
• heteroaryl for example thienyl, furanyl, isoxazolyl, pyridyl and benzothienyl
• R 5 groups are those wherein R 5 is C 1-4 alkyl, aryl, for example phenyl and dihydrobenzofuranyl, heteroaryl, for example thienyl, furanyl, isoxazolyl, pyridyl and benzothienyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, for example piperidinyl, morpholinyl and piperazinyl, phenyl-(C 1-2 alkyl)-, for example benzyl, heteroaryl-(C 1-2 alkyl)- or —XR 6 .
• R 5 in the formula (V) is C 1-4 alkyl, phenyl, thienyl, furanyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydrobenzofuranyl, phenyl-CH 2 —, furanyl-CH 2 —, phenyl-C(O)—C(O)—, thienyl-C(O)—C(O)— or —XR 6 .
• R 5 groups are those wherein R 5 is C 1-4 alkyl, phenyl, thienyl, furanyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydrobenzofuranyl, phenyl-CH 2 —, furanyl-CH 2 — or —XR 6 .
• R 5 in the formula (V) is phenyl-CH 2 —, furanyl-CH 2 —, —C(O)—C(O)-thienyl or —XR 6 .
• Examples of most preferred R 5 groups are those wherein R 5 is phenyl-CH 2 —, furanyl-CH 2 — or —XR′.
• X in the formula (V) is —CO—, —S(O)— or —S(O) 2 —.
• X is —CO— or —S(O) 2 —.
• R 6 in the formula (V) is a group —NR′R′′ and either R′ or R′′ includes an aryl, heteroaryl, carbocyclyl or heterocyclyl moiety it is typically unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro and cyano.
• the aryl, heteroaryl, carbocyclyl or heterocyclyl moiety is unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy and nitro.
• substituents selected from fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy and nitro.
• the aryl, heteroaryl, carbocyclyl or heterocyclyl moiety is unsubstituted or substituted by one or two substituents selected from fluorine, chlorine, bromine, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 alkylthio, C 1-2 haloalkyl and nitro.
• substituents selected from fluorine, chlorine, bromine, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 alkylthio, C 1-2 haloalkyl and nitro.
• An example of more preferred substitution is when the aryl, heteroaryl, carbocyclyl or heterocyclyl moiety is unsubstituted or substituted by a single fluoro, chloro, methyl, methoxy or nitro substituent.
• R′ or R′′ is a heteroaryl or heterocyclyl group, it is attached via a carbon atom.
• R′ and R′′ in the group —NR′R′′ in the formula (V) are not both hydrogen.
• each R′ and R′′ is the same or different and represents hydrogen, C 1-4 alkyl, aryl, heteroaryl, carbocyclyl, aryl-(C 1-4 alkyl)- or heteroaryl-(C 1-4 alkyl)-.
• Examples of typical R′ and R′′ groups are those wherein each R′ and R′′ is the same or different and represents hydrogen, C 1-4 alkyl, phenyl, heteroaryl, for example thienyl, carbocyclyl, for example cyclohexyl or cyclopentyl, or phenyl-(C 1-4 alkyl)-.
• R′ and R′′ groups are those wherein each R′ and R′′ is the same or different and represents hydrogen, C 1-4 alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH 2 )—.
• each R′ and R′′ is the same or different and represents hydrogen, C 1-4 alkyl, phenyl, phenyl-CH 2 —, cyclohexyl or cyclopentyl. More preferably, one of R′ and R′′ represents hydrogen.
• one of R′ and R′′ is hydrogen and the other is C 1-4 alkyl, phenyl, phenyl-CH 2 —, cyclohexyl or cyclopentyl.
• one of R′ and R′′ is hydrogen and the other is C 1-4 alkyl, phenyl, thienyl or phenyl-CH 2 —.
• R 6 in the formula (V) is C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-4 alkyl)-, heteroaryl-(C 1-4 alkyl)-, carbocyclyl-(C 1-4 alkyl)-, heterocyclyl-(C 1-4 alkyl)-, aryl-(C 1-4 hydroxyalkyl)-, heteroaryl-(C 1-4 hydroxyalkyl)-, carbocyclyl-(C 1-4 hydroxyalkyl)-, heterocyclyl-(C 1-4 hydroxyalkyl)-, aryl-(C 1-4 alkyl)-O—, heteroaryl-(C 1-4 alkyl)-O—, carbocyclyl-(C 1-4 alkyl)-O—, heterocyclyl-(C 1-4 alkyl)-O— or —NR′R
• R 6 groups are those wherein R 6 is C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-4 alkyl)-, heteroaryl-(C 1-4 alkyl)-, carbocyclyl-(C 1-4 alkyl)-, heterocyclyl-(C 1-4 alkyl)- or —NR′R′′ wherein R′ and R′′ are as defined above.
• R 6 in the formula (V) is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, aryl, for example phenyl, naphthyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl and indolyl, heteroaryl, for example thienyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl and benzofuranyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, for example piperazinyl, piperidinyl, morpholinyl and 1H-benzo[d ⁇ imidazol-2(3H)-onyl, phenyl-(C 1-2 alkyl)-, phenyl-(C 1-2 alkyl)-O—, phenyl-(C
• R 6 groups are those wherein R 6 is C 1-4 alkyl, aryl, for example phenyl and dihydrobenzofuranyl, heteroaryl, for example thienyl, furanyl, isoxazolyl, pyridyl and benzothienyl, carbocyclyl, for example cyclopentyl and cyclohexyl, heterocyclyl, for example N-heterocyclyl, phenyl-(C 1-2 alkyl)-, for example benzyl, heteroaryl-(C 1-2 alkyl)- or —NR′R′′ wherein R′ and R′′ are as defined above.
• R 6 in the formula (V) is C 1-4 alkyl, C 1-4 alkoxy, phenyl, naphthyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl, indolyl, thienyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuranyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, phenyl-(C 1-2 alkyl)-, phenyl-CH 2 —CH(OH)—, phenyl-CH(OH)—CH 2 —, phenyl-(C 1-2 alkyl)-O—, 1H-benzo[d]imidazol-2(3H)-onyl or —NR′R′′ wherein R′ and R′′ are
• R 6 groups are those wherein R 6 is C 1-4 alkyl, phenyl, thienyl, furanyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydrobenzofuranyl, isoxazolyl, piperidinyl, for example N-piperidinyl, morpholinyl, for example N-morpholinyl, piperazinyl, for example N-piperazinyl, or —NR′R′′ wherein R′ and R′′ are as defined above.
• Preferred compounds of the formula (V) are those in which:
• the aryl moiety in the R 1 group being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl or C 1-6 haloalkoxy;
• the aryl and heteroaryl moieties in the groups R 5 and R 6 being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl, di(C 1-6 alkyl)carbomyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′, —S(O)NR′R′′, —S(O) 2 NR′R′′, —NH—S(O) 2 R′′ or —NH—CO—R′, wherein each R′ and R
• the carbocyclyl and heterocyclyl moieties in the groups R 5 and R 6 being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, nitro, cyano, carbamoyl, mono(C 1-6 alkyl)carbamoyl, di(C 1-6 alkyl)carbomyl, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, oxo, —CO 2 R′, —CONR′R′′, —S(O)R′, —S(O) 2 R′, —S(O)NR′R′′, —S(O) 2 NR′R′′, —NH—S(O) 2 R′ or —NH—CO—R′
• alkyl moieties in the aryl-(C 1-4 alkyl)-, heteroaryl-(C 1-4 alkyl)-, carbocyclyl-(C 1-4 alkyl)-, heterocyclyl-(C 1-4 alkyl)- groups of R 6 being unsubstituted or substituted by one or two hydroxy substituents.
• the aryl, heteroaryl and carbocyclyl moieties in the groups R′ and R′′ are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C-6 haloalkyl, C 1-6 haloalkoxy, nitro and cyano.
• the aryl moieties in the groups R 5 and R 6 being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-6 alkyl, C 2-7 acyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro, cyano, —CO 2 R′, —S(O)R′, —S(O) 2 R′ and —S(O) 2 NR′R′′, wherein each R′ and R′′ is the same or different and represents hydrogen or C 1-4 alkyl;
• heteroaryl moieties in the groups R 5 and R 6 being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro and cyano; and
• the carbocyclyl and heterocyclyl moieties in the groups R 5 and R 6 being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro, cyano and oxo; and
• the phenyl, heteroaryl and carbocyclyl moieties in the groups R′ and R′′ are unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy and nitro.
• Particularly preferred compounds of formula (V) are compounds of formula (Va) are pharmaceutically acceptable salts thereof
• the phenyl moiety in the group R′ being unsubstituted or substituted by a single fluorine, chlorine, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 alkylthio, C 1-2 haloalkyl or C 1-2 haloalkoxy substituent;
• the aryl moieties in the groups R 5 and R 6 being unsubstituted or substituted by 1,2 or 3 substituents selected from fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 2-4 acyl, hydroxy, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, mono(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, nitro, —CO 2 R′, —S(O) 2 R′ and —S(O) 2 NH 2 , wherein R′ represents C 1-2 alkyl;
• heteroaryl moieties in the groups R 5 and R 6 being unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, C 1-2 alkyl, C 1-2 haloalkyl and di(C 1-2 alkyl)amino; and
• heterocyclyl and carbocyclyl moieties in the R 6 group being unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and nitro.
• R 1 in the formula (Va) is phenyl, n is 0, R 4 is hydrogen and R 5 is —CO— phenyl or —CO—NH-phenyl, wherein the phenyl group in R 5 is unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, —CO 2 R′ or —S(O) 2 R′, wherein each R′ is the same or different and represents C 1 -C 2 alkyl.
• Preferred compounds of the formula (V) are optically active isomers.
• preferred compounds of formula (V) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.
• the compounds of the formula (V) can, if desired, be used in the form of solvates.
• a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
• Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tataric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
• Pharmaceutical acceptable bases include alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.
• component (b) is:
• the compounds of formulae (I), (II), (III) and (IV) are known compounds. They are disclosed, for example, in WO 00/195910, WO 00/004900, WO 03/053344, U.S. Pat. No. 4,324,794 and WO 01/00612, and can be prepared by the processes set out in those documents.
• WO 00/195910, WO 00/004900, WO 03/053344, U.S. Pat. No. 4,324,794 and WO 01/00612 are incorporated herein by reference. Any of the compounds disclosed as fusion protein inhibitors in those documents can be used in the present invention.
• amino acid of formula (II′) can then be reacted with a suitable chlorinating agent, such as oxalyl chloride, followed by reaction with a 2-aminobenzophenone of formula (III′)
• the compound of formula (IV′) can then be subjected to ammonolysis followed by ring closure in acetic acid containing ammonium acetate to obtain the protected benzodiazepine of formula (V′)
• the compound of formula (V′) can then be deprotected using hydrogen bromide in acetic acid to yield the deprotected amine of formula (VI′).
• Compounds of formula (V), in which R 5 is XR 6 and X is —CO— can be prepared by reacting a compound of formula (VI′), as defined above, with an acid anhydride in a suitable solvent, preferably pyridine at ambient temperature, or with an acid chloride in a suitable solvent in the presence of a base, preferably in THF at ambient temperature with triethylamine present.
• a suitable solvent preferably pyridine at ambient temperature
• an acid chloride in a suitable solvent in the presence of a base, preferably in THF at ambient temperature with triethylamine present.
• the compounds can be produced by reaction of a compound of formula (VI′) with an acid in a suitable solvent in the presence of a base and a coupling agent, preferably in THF at ambient temperature with triethylamine and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) present.
• a base preferably in THF at ambient temperature
• HBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate
• the compound of formula (V) is a tertiary urea.
• R 6 is NH—R′
• such compounds may be prepared by the reaction of a compound of formula (VI′) with an isocyanate. This reaction is preferably carried out in THF at ambient temperature.
• the isocyanate may be prepared in situ from the relevant amine and phosgene, in the presence of a base, usually triethylamine, again in THF.
• R 5 is not XR 6
• a compound of formula (VI′) can be reacted with a compound of formula R 5 -L, wherein L is a leaving group such as a chlorine atom, a mesylate group or a triflate group.
• L is a leaving group such as a chlorine atom, a mesylate group or a triflate group.
• R 5 is aryl or heteroaryl
• L can be —B(OH) 2 and the reaction may take place in the presence of copper acetate.
• Such boronic acid coupling reactions will, of course, be familiar to those of skill in the art.
• R 5 is aryl or heteroaryl
• a Buchwald reaction or by reaction of a compound of formula (VI′) with an appropriate fluoroaryl or fluoroheteroaryl compound.
• Compounds wherein R 5 is a heteroaryl group may also be prepared by reaction of a compound of formula (VI′) with a suitable chloroheteroaryl or bromoheteroaryl compound.
• Compounds wherein R 5 is a carbocyclyl group may also be prepared by known methods, for example a compound wherein R 5 is cyclohexyl may be prepared by the reaction of a compound of formula (VI′) with cyclohexanone in the presence of a reducing agent.
• Compounds of formula (V) in which the R 5 group is aryl-(C 1-6 alkyl)-, heteroaryl-(C 1-6 alkyl)-, carbocyclyl-(C 1-6 alkyl)-, heterocyclyl-(C 1-6 alkyl)- can also be prepared by the reaction of a compound of formula (VI′) with an aldehyde in the presence of a reducing agent.
• a compound of formula (VI′) with an aldehyde in the presence of a reducing agent.
• such reactions between compounds of formula (VI′) and aldehydes are carried out in a mixture of dichloromethane and acetic acid in the presence of sodium (triacetoxy)borohydride at ambient temperature.
• the described route to the claimed compounds provides an adequate synthesis for laboratory scale preparations, an alternative route was sought which has potential as a manufacturing route.
• the same starting material (2-amino-benzophenone) (1) is used in both, however in the alternative route, the benzodiazepine ring system is formed by reaction initially with bromoacetyl bromide (or an equivalent reagent) followed by ring closure with ammonia. These reactions are carried out in a suitable solvent, such as dichloromethane, and at a suitable temperature which may range from ⁇ 20 to 150° C.
• a suitable solvent such as dichloromethane
• a suitable temperature which may range from ⁇ 20 to 150° C.
• the unsubstituted benzodiazepine is reacted with a base, and an alkylating agent.
• DKR Dynamic Kinetic Resolution
• the optically amine thus formed may then be transformed into a desired derivative, such as an amide or urea.
• a desired derivative such as an amide or urea.
• the amide formations may be carried out using a suitable carboxylic acid and a coupling reagent, or a carbonyl chloride or other suitable reagent, and the ureas prepared using aeither a suitable isocyanate, or alternatively reaction with phosgene followed by a suitable amine.
• These derivatives thus formed may then have the protecting group removed. This may be carried out in the presence of a Lewis Acid, such as aluminium chloride, boron trifluoride, titanium tetrachloride, or the like. These reactions are carried out in a suitable inert solvent, such as dichloromethane. Reaction temperatures may range from ⁇ 20 to 150° C., but are typically carried out at room temperature or below.
• a Lewis Acid such as aluminium chloride, boron trifluoride, titanium tetrachloride, or the like.
• a suitable inert solvent such as dichloromethane. Reaction temperatures may range from ⁇ 20 to 150° C., but are typically carried out at room temperature or below.
• component (a) is 1-cyclopropyl-3-[1-(4-hydroxy-butyl)-1H-benzoimidazol-2-ylmethyl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one, 2-[2-(1,2-dihydro-benzotriazol-1-ylmethyl)-benzoimidazol-1-yl]]ethyl ⁇ -diethyl-amine, ⁇ 2-[2-(3-iodo-2,3-dihydro-indazol-1-ylmethyl)-benzimidazol-1-yl]-ethyl ⁇ -dimethyl-amine or a pharmaceutically acceptable salt thereof and component (b) is (S)-1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea, (S)-2
• the present invention also provides a pharmaceutical composition according to the invention, for use in the treatment of the human or animal body. Also provided is the use of (a) a said RSV fusion protein inhibitor and (b) a said benzodiazepine derivative, in the manufacture of a medicament for use in treating or preventing an RSV infection.
• the present invention also provides a method of treating or preventing an RSV infection in a patient, which method comprises the administration to said patient of (a) a said RSV fusion protein inhibitor and (b) a said benzodiazepine derivative.
• the amount of component (a) in the composition of the invention is from 0.025 wt % to 10 wt %, preferably from 0.25 wt % to 5 wt %, more preferably from 1 wt % to 3.5 wt %, for example about 2.5 wt %, based on the total weight of the composition.
• the amount of component (b) in the composition of the invention is from 0.025 wt % to 10 wt %, preferably from 0.25 wt % to 5 wt %, more preferably from 1 wt % to 3.5 wt %, for example about 2.5 wt %, based on the total weight of the composition.
• the total amount of components (a) and (b) in the composition of the invention is from 0.05 to 20 wt %, preferably from 0.5 to 10 wt %, more preferably from 2 to 7 wt %, for example about 5 wt %, based on the total weight of the composition.
• RSV is prevalent among children younger than two years of age, adults suffering from asthma, chronic obstructive pulmonary disorder (COPD) or immunodeficiency and the elderly. It is a particularly serious risk amongst children who suffer from chronic lung disease. Accordingly, the said composition or medicament is typically for use in treating a patient who is a child under two years of age, patients with asthma, COPD or immunodeficiency the elderly or persons in long term care facilities. Typically, said child suffers from chronic lung disease.
• COPD chronic obstructive pulmonary disorder
• anti-RSV prophylaxis is recommended for infants born at 32 weeks of gestation or earlier, until they reach 6 months of age, the elderly, persons with immunedeficiency and those in long term care facilities. Accordingly, the said composition or medicament is typically for use in preventing RSV infection in an infant less than 6 years of age, who was born after 32 weeks of gestation or less, the elderly, persons with immunosufficiency and those in long term care facilities.
• the benzodiazepine derivatives disclosed above are the first class of compounds with a novel mode of action. Accordingly, the compositions of the invention are characterized by a very low resistance profile, which makes them particularly suitable for therapeutic and prophylactic applications.
• component (a) and (b) are administered separately.
• component (a) can be administered up to 24 hours before component (b).
• component (b) can be administered up to 24 hours before component (a). More usually, when components (a) and (b) are administered separately, they are administered within 12 hours, preferably within 6 hours, of each other.
• the present invention therefore also provides a product comprising (a) a said RSV fusion protein inhibitor and (b) a said benzodiazepine derivative for separate, simultaneous or sequential use in the treatment of the human or animal body.
• a product comprising (a) a said RSV fusion protein inhibitor and (b) a said benzodiazepine derivative for separate, simultaneous or sequential use in the treatment of the human or animal body.
• said product is for separate, simultaneous or sequential use in treating or preventing an RSV infection.
• a said RSV fusion protein inhibitor in the manufacture of a medicament for use in treating or preventing an RSV infection by co-administration with a said benzodiazepine derivative.
• the present invention also provides the use of a said benzodiazepine derivative in the manufacture of a medicament for use in treating or preventing an RSV infection, by co-administration with a said RSV fusion protein inhibitor.
• a first formulation is typically provided which contains from 0.025 wt % to 10 wt %, preferably from 0.25 wt % to 5 wt %, more preferably from 1 wt % to 3.5 wt %, for example about 2.5 wt %, of a said RSV fusion protein inhibitor, based on the total weight of the formulation.
• a second formulation is typically provided which contains from 0.025 wt % to 10 wt %, preferably from 0.25 wt % to 5 wt %, more preferably from 1 wt % to 3.5 wt %, for example around 2.5 wt %, of a said benzodiazepine derivative, based on the total weight of the formulation.
• the two formulations can be administered separately in any order.
• compositions and medicaments of the invention have an activity greater than the combined individual activities of compounds (a) and (b).
• components (a) and (b) typically interact synergistically.
• component (a) and component (b) are each present in an amount producing a synergistic therapeutic effect in treating or preventing an RSV infection.
• the anti-RSV compositions of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
• the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
• the compounds may also be administered as suppositories.
• administration is by intravenous, intranasal or intrabronchial means.
• formulations for treating or preventing RSV can advantageously be administered intranasally.
• the present invention therefore also provides an inhaler or nebuliser containing a medicament which comprises (i) a composition of the invention comprising component (a) and component (b), as defined above, and (ii) a pharmaceutically acceptable carrier or diluent.
• the anti-RSV compositions of the invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
• solid oral forms may contain, together with the active compound(s), diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
• Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
• Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
• the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
• Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
• the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
• Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
• the anti-RSV compositions of the invention are solubilised in a carrier containing (a) a pharmaceutically acceptable oil selected from esterification or polyether products of glycerides with vegetable oil fatty acids of chain length C 8 -C 10 and (b) a pharmaceutically acceptable surfactant selected from oleate and laurate esters of a polyalcohol copolymerized with ethylene oxide.
• a pharmaceutically acceptable oil selected from esterification or polyether products of glycerides with vegetable oil fatty acids of chain length C 8 -C 10
• a pharmaceutically acceptable surfactant selected from oleate and laurate esters of a polyalcohol copolymerized with ethylene oxide.
• Particularly preferred carriers contain Labrafil as the oil and Tween 20 or Tween 80 as the surfactant.
• the anti-RSV compositions of the invention also be suspended in PEG 400 for oral administration.
• a therapeutically effective amount of an anti-RSV composition of the invention is administered to a patient.
• a typical dose is from about 0.001 to 50 mg, typically 0.5 to 30 mg, preferably 1 to 20 mg active ingredient per kg of body weight, according to the activity of the specific composition, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
• daily dosage levels are from 5 mg to 2 g active ingredient.
• RSV enters the host cell via attachment to and fusion with the host cell membrane.
• the effect of an inhibitor on the specific virus-cell fusion event can be qualitatively determined by using a fluorescence de-quenching system.
• This assay takes advantage of the fact that RSV binds to cells at 4° C. and at 37° C. but that fusion may only occur at concentrations above 18° C.
• RSV labelled with octadecyl rhodamine dye (R18) is pre-incubated with Hep-2 cells seeded in a 6-well plate for 1 hour at 4° C. to allow binding to occur. Unattached virus is removed by washing the cell monolayer. The inhibitor is then added to the virus-cell complexes prior to transferring the plates to 37° C. for 1 hour in order to induce fusion. Virus-cell fusion can be observed directly under a fluorescence microscope. Fluorescence emission is quenched when 2 identical fluorophores are in close proximity. Upon fusion of the labelled virus with the cell membrane, the distance between fluorophores is increased due to dye spread and there is a decrease in quenching.
• the inner 60 wells of 96 well tissue culture plates are seeded with Hep-2 cells at 4 ⁇ 10 4 cells/well for compound activity and toxicity studies in 100 ⁇ l of medium and incubated at 37° C. overnight or until nearing confluency.
• Cells are infected with 25 ⁇ l RSV, e.g. the RSS strain, previously titrated to give 80% cell kill.
• 25 ⁇ M of test compound are added.
• the final DMSO concentration is 0.5%.
• Some 200 ⁇ l of sterile distilled water is added to the outer wells of the plate and incubated at 37° C. for 6 days.
• Some 0.25 ⁇ l/ml PMS are added to stock XTT solution, final conc. 25 ⁇ M PMS. Then 25 ⁇ l warmed XTT/PMS solution is added to each well and incubated for 1 hour at 37° C.
• This assay was set up using all 96 wells of flat-bottomed 96-well plates. The outer wells were not subjected to any greater amount of evaporation than the inner wells during the 3 day assay period. (ie. No “edge effect” seen).
• GM Growth Medium
• DMEM Dulbecco's MEM
• Glutamax-1 Glutamax-1
• Sodium Pyruvate 1000 mg/l glucose and pyridoxine (Invitrogen, catalogue number 21885-025) and supplemented with 10% FBS.
• tissue culture In tissue culture, the cells adhere to the tissue culture flask and were grown at 37° C., 5% CO 2 until 90% confluent.
• Monolayers were washed with 20 ml sterile PBS to remove serum and treated with 1 ml trypsin to detach cells from the flask.
• Cells were suspended in a small known volume of growth media and counted using a haemocytometer. The cell suspension was made up to the desired concentration in growth medium and added to wells by multichannel pipette. Brief, gentle shaking encouraged the cells to disperse more evenly across the well.
• RSV RSV strain provided by Virogen Ltd
• the m.o.i. was calculated by prior titration of the virus stock (by the ELISA assay method) as the virus input required to achieve a window of at least 0.8 OD units between infected and uninfected control wells.
• Multiplicity ⁇ ⁇ of ⁇ ⁇ Infection plaque ⁇ ⁇ forming ⁇ ⁇ units ⁇ ⁇ per ⁇ ⁇ well ⁇ ⁇ ( pfu ⁇ / ⁇ well ) number ⁇ ⁇ of ⁇ ⁇ cells ⁇ ⁇ per ⁇ ⁇ well
• Example 9c 25 ⁇ l (50 ⁇ l in Example 9c) of diluted virus was added to infected wells by multichannel pipette; 25 ⁇ l (50 ⁇ l in Example 9c) of Growth Medium was added to uninfected, cell control wells by multichannel pipette.
• Compound “A” was titrated horizontally across the plate and Compound “B” was titrated vertically down the plate, creating a chequerboard.
• the 2 compounds were titrated at either 1 ⁇ 2-log or doubling dilutions either across (horizontally) or down the plate (vertically) in the presence of virus.
• Each compound dilution was set up in duplicates or triplicates. For triplicates 3 identical plates were set up. Duplicates were set up as dublicate wells on the same plate. The dilution range covered concentrations from just above the compound IC50 to below the compound IC50 and included a 0 ⁇ M control for each compound.
• Example 9c 12.5 ⁇ l (25 ⁇ l in Example 9c) of GM (containing 2% DMSO) was added to wells receiving 0 ⁇ M Compound “A” or 0 ⁇ M Compound “B”. 25 ⁇ l (50 ⁇ l in Example 9c) GM (containing 2% DMSO) was added to wells containing neither compound.
• Virus infected, untreated wells served as the virus control (VC); Uninfected, untreated wells serve as the cell control (CC).
• CC cell control
• the difference in absorbance between CC and VC wells constitutes the assay window.
• Acetone/methanol was discarded from wells into Virkon and wells were washed with PBS as above.
• Block solution was discarded down the sink and diluted primary antibody was added directly to wells (ie. no washing required).
• RSV mouse monoclonal antibody NCL-RSV3 (Novocastra ) was diluted 1/400 in PBS/2% Marvel/0.05% Tween and 50 ⁇ l was added per well. Plates were incubated at 37° C. in a shaking incubator for 90 mins.
• Antibody was discarded down the sink and plates were washed 4 times by immersion in PBS/0.05% Tween.
• DAKo rabbit anti-mouse HRP conjugate (DAKO catalogue number P0260) was diluted 1/1000 in PBS/2% Marvel/0.05% Tween and 50 ⁇ l was added per well. Plates were incubated at 37° C. in a shaking incubator for 60mins.
• Antibody was discarded down the sink and plates were washed 6 times by immersion in PBS/0.05% Tween.
• Substrate (SigmaFast OPD) was prepared in advance by dissolving 1 urea tablet in 20 mL water. 1 OPD tablet was added to the urea solution just prior to use (NB. OPD was light sensitive) and vortexed to mix. 50 ⁇ l of substrate was added per well.
• reaction was stopped by addition of 25 ⁇ l/well of 20% sulphuric acid, once sufficient colour had developed but while cell control background was still low ( ⁇ 5 minutes).
• the wells were emptied, washed in tap water and the monolayers stained with 50 ⁇ l/well of 2% crystal violet in 20% methanol/water for at least 1 hour. The wells were then washed and air-dried and the monolayers examined under the microscope for indications of cell toxicity.
• the assay window was calculated by subtracting the meaned cell control (CC) from the meaned virus control (VC). For each compound, the meaned CC was subtracted from the meaned values for each concentration point. The % of control was then calculated for each concentration point as a percentage of the window. % of control was plotted against compound concentration. A straight line was fitted to the curve and the slope and intercept functions were used to calculate the IC50.
• the IC50 for Compound “A” was calculated for each background concentration of Compound “B”. Similarly, the IC50 for Compound “B” was calculated for each background concentration of Compound “A”.
• Compound B has an ELISA IC50 of 2 ⁇ M against the RSV RSS strain.
• Compound A has an ELISA IC50 of 0.5 ⁇ M against the RSV RSS strain.
• the IC50 of Compound B is reduced from 0.5 ⁇ M to at least 0.16 ⁇ M (3.2-fold decrease).
• concentrations of Compound B below its IC50 (0.3, 0.1 ⁇ M) the IC50 of Compound A is reduced from 2 ⁇ M to at least 0.65 ⁇ M (3-fold decrease).
• Compound B has an ELISA IC50 of 1.4 ⁇ M against the RSV RSS strain.
• Compound A has an ELISA IC50 of 0.015 ⁇ M against the RSV RSS strain.
• the IC50 of Compound A is reduced from 0.015 ⁇ M to at least 0.0007 ⁇ M (21.4-fold decrease).
• concentrations of Compound A below its IC50 0.01, 0.003, 0.001, 0.0003 ⁇ M
• the IC50 of compound B is reduced from 1.4 ⁇ M to at least 0.26 ⁇ M (5.4-fold decrease).
• Compound A has an ELISA IC50 of 1 ⁇ M against the RSV RSS strain.
• Compound B has an ELISA IC50 of 0.08 ⁇ M against the RSV RSS strain.
• the IC50 of Compound B is reduced from 0.08 ⁇ M to at least 0.03 ⁇ M (2.66fold decrease).
• the IC50 of Compound A is reduced from 1 ⁇ M to at least 0.3 ⁇ M (3.33-fold decrease).
• FIC Lowest ⁇ ⁇ IC50 ⁇ ⁇ Cpd ⁇ ⁇ A COMBINATION IC50 ⁇ ⁇ Cpd ⁇ ⁇ A ALONE + Lowest ⁇ ⁇ IC50 ⁇ ⁇ Cpd ⁇ ⁇ B COMBINATION IC50 ⁇ ⁇ Cpd ⁇ ⁇ B ALONE

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